We read with interest Simuni et al.'s report on the application of the Neuronal α‐Synuclein Disease‐Integrated Staging System (NSD‐ISS) to the Parkinson's Progression Markers Initiative (PPMI) cohort from baseline to 5 years. 1 The NSD‐ISS uses the α‐synuclein seed amplification assay (αSyn‐SAA), which detects pathological α‐synuclein, as the ‘S' in a triaxial ‘S‐D‐G' framework (synuclein, DAT scan, genetic status). 2 , 3 Simuni et al. suggest their data validate the use of NSD‐ISS for recruitment into disease‐modification trials. We contend that they support its refutation.
For future disease‐modification trials, a valid disease staging system must reflect the natural distribution of disease progression, where most individuals at baseline cluster in early disease stages (Stages 1 or 2), with fewer in higher disease stages. Reliance on largely static biomarkers makes such distribution by NSD‐ISS impossible. The ‘S', ‘D', and ‘G' axes exhibit minimal longitudinal change: once αSyn‐SAA is positive, it never becomes negative; SNCA genotype is fixed; and DAT SPECT, which changes only modestly over time, is treated in a binary fashion (normal vs. abnormal). The only dynamic features are the clinical manifestations and functional impairment, divided into mild, moderate, and severe, reflected in NSD‐ISS Stages 3 to 6. It is not surprising, therefore, that in the de novo PPMI population, the NSD‐ISS classifies more than 70% of baseline patients at Stage 3 or higher (Stage 3: 56%; Stage 4: 13%; Stage 5+: just under 2%). 1
Furthermore, a valid disease staging system should exhibit unidirectional progression. The NSD‐ISS also fails here. Levodopa treatment led to “stage regression” in nearly 50% of the PPMI cohort: 8% of patients initially classified as NSD‐ISS Stage 3 and 41% of those at Stage 4 shifted to earlier stages. 1 This reversibility, driven by symptomatic therapy, undermines the claim that the system reflects the underlying progressive “biology” of Parkinson's disease (NSD‐ISS equates pathology to biology). Else, the framework would have to reclassify levodopa as disease modifying.
The mismatch between the predicted and actual performance of the NSD‐ISS raises serious concerns about construct validity. These concerns are amplified by the absence of any correlation between the NSD‐ISS stages and established fluid biomarkers of motor or cognitive Parkinson's progression. Neither serum neurofilament light chain 4 nor cerebrospinal fluid levels of Aβ42, 5 total tau, or phosphorylated tau 6 differed across NSD‐ISS stages, as inconspicuously noted in Supplemental Table 2a. 1
Additionally, the authors of the framework previously acknowledged that many individuals in stage 1A—αSyn‐SAA‐positive but asymptomatic—could remain in this stage indefinitely. 2 This admission alone should question their conclusion of using NSD‐ISS as a disease staging system to support early enrollment of individuals into clinical trials of disease‐modifying interventions.
“Our analysis supports the utility of NSD‐ISS in defining the stages of disease progression, suggesting the value of NSD‐ISS as a potential research tool for drug development.” 1
If these results do not falsify the NSD‐ISS as a staging framework, what would? Rather than questioning their model, the authors question the population. Because fewer than 10% of participants met criteria for Stage 2A (S+, D–, and “subtle clinical symptoms”), 1 the PPMI now aims to recruit an additional 1000 individuals to chase the elusive disease stage their own model presumes must exist in the wild.
We suggest this search is in vain. The problem lies not in the population but in the framework itself. If ‘NSD' is solely defined by the presence of a biomarker of αSyn pathology—one that is non‐progressive, found in heterogeneous populations, and may never result in clinical symptoms—then the definition is flawed. The logic becomes circular: wherever the biomarker is found, the disease is assumed to exist. Such a construct is self‐reinforcing and immune to falsification.
Author Roles
(1) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
A.J.E.: 1A.
F.C., S.J.F., A.I., G.M.H., A.J.L.: 1B.
Acknowledgments
The authors did not use artificial intelligence (AI) in the generation of this letter.
Relevant conflicts of interest/financial disclosures: A.J.E. has received grant support from the National Institutes of Health (NIH) and The Michael J. Fox Foundation; personal compensation as a consultant/scientific advisory board member for Mitsubishi Tanabe Pharma America (formerly Neuroderm), Amneal, Acorda, AbbVie, Bial, Kyowa Kirin, Supernus (formerly USWorldMeds), NeuroDiagnostics, Inc. (SYNAPS Dx), Intrance Medical Systems, Inc., Merz, Praxis Precision Medicines, Citrus Health, and Herantis Pharma; Data Safety Monitoring Board (Chair) of AskBio; and publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer. He is co‐inventor of the patent “Compositions and methods for treatment and/or prophylaxis of proteinopathies”. He co‐founded REGAIN Therapeutics to fund preclinical studies but relinquished the right to any personal income from future treatments. He serves on the editorial boards of the Journal of Parkinson's Disease, Journal of Alzheimer's Disease, European Journal of Neurology, Movement Disorders Clinical Practice, and JAMA Neurology. F.C. has organization relationships with Member of the International Parkinson and Movement Disorder Society, Brazilian Academy of Neurology, and the American Academy of Neurology. S.J.F. reports no disclosures. A.I. reports no disclosures. G.M.H. has received grant support from the Aligning Science Across Parkinson's (ASAP) initiative, The Michael J. Fox Foundation, Defeat MSA Canada and Defeat MSA Australia‐New Zealand, NIH, the Medical Research Future Fund Australian Parkinson's Mission, and the National Health and Medical Research Council of Australia (NHMRC) ‐ Investigator, Program, Dementia Team, EU Joint Program on Neurodegenerative Disease Research, National Institute for Health and Care Research (NIHR) Collaborative Research Program, and Centre of Research Excellence; personal compensation as a consultant/committee member for the Australian Government Department of Health and Aged Care and the Australian Government National Health and Medical Research Council; and publishing royalties from Elsevier, Academic Press, and Oxford University Press. She serves on the editorial boards of Acta Neuropathologica, IBRO Reports, Journal of Neural Transmission, Journal of Parkinson's Disease, Neurobiology of Disease, Neuropathology and Applied Neurobiology, Science Advances, and Translational Neuroscience. A.J.L. has a consultancy agreement with Britannia Pharmaceuticals and has received honoraria from Bial and Convatec.
Funding agency: None.
Data Availability Statement
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data sharing is not applicable to this article as no new data were created or analyzed in this study.